PROJECT SUMMARY Emotion-regulatory deficits are a hallmark of mood and anxiety disorders. Thus, the ability to regulate emotional responses according to one's goals and to effectively override automatic responses to emotional events is paramount to mental health and wellbeing. Function of the lateral prefrontal cortex (LPFC) has been shown to play a pivotal role in supporting goal-oriented and flexible behavior. Moreover, extant data implicates LPFC dysfunction in the pathophysiology of depression and anxiety. However, studies establishing the specific and causal contributions of LPFC function to emotion regulation are sorely lacking. This proposal will illuminate the causal role of LPFC representations for goal-oriented behavioral regulation during affective processing and identify mediating neural mechanisms. The proposed studies will test the central hypothesis that task-relevant emotion-regulatory goals are dynamically represented in mid-LPFC, from which they are conveyed to topographically organized dorsomedial PFC (dmPFC) and integrated with affect signals from the amygdala. This hypothesis is based on recent insights into PFC organization and documented neuroanatomical projections. The experiments will employ a behavioral task that is sensitive to LPFC function and that indexes the degree of influence of prepotent emotional stimuli on behavior depending on the task goal. The LPFC- dmPFC-amygdala circuitry will be examined using a combination of advanced neuroimaging multi-voxel pattern analysis (MVPA) combined with transcranial magnetic stimulation (TMS), and behavioral studies of patients with focal PFC lesions. This combination of novel data acquisition methods and analytic approaches will reveal the functional causal contributions of specific PFC regions and provide a precise mechanistic account of how the LPFC contributes to adaptive emotional responding. The proposed studies will thus fill a substantial gap in emotion regulation research, and further the development of a model that can be applied to optimize and personalize treatment for individuals who suffer from mood and anxiety disorders associated with PFC dysfunction.